New biotransformation products of nemadectins.

Selected nemadectins (formerly LL-F28249 series) have been fed to a panel of microorganisms with the aim of generating new derivatives. In addition to products resulting from the oxidation of the terminal methyl group (C-29), a unique phosphorylated nemadectin was isolated. The phosphate group was determined to be at C-23 by HMBC between phosphorus and H-23. Milbemycin or nemadectin derivatives with natural substituents involving the 23-hydroxyl group were hitherto unknown.     

Meloxicam: metabolic profile and biotransformation products in the rat

1. The metabolic fate of ^14C-labelled meloxicam was investigated in the urine and bile of rat following oral and intraduodenal administration. Structural elucidation of metabolites was performed by nuclear magnetic resonance, mass spectrometry (electron impact and fast atom bombardment).

2. A mean total of 76·3% ^14C-radioactivity was recovered in urine over 96?h, with the remainder in the faeces. The metabolic pattern in the excreta was independent of dose (1 versus 10?mg/kg) and collection period (0–8 versus 24–48?h). In bile one of the main metabolites was absent.

3. Meloxicam underwent extensive metabolism with only small amounts of unchanged drug recovered in the urine (<0·5%) or bile (4·5%). Principal routes of biotransformation were: oxidation of the 5-methyl group of the N-heteroaryl-carbamoyl side chain to yield the 5'-hydroxymethyl derivative (33% of metabolites in urine, 22% in bile) and the 5'-carboxy derivative (16% in urine, 49% in bile). Oxidative cleavage of the benzothiazinering yielded an oxamic acid metabolite in urine (23·5%), which was not present in bile.

4. The introduction of a methyl-group into the N-heteroaryl-carbamoyl side chain increased lipophilicity and facilitated metabolic excretion compared with structurally related compounds.     

一株白僵菌对雄甾烯二酮转化产物的研究

利用白僵菌Beauveria bassiana HCCB00059对雄甾烯二酮（4AD）进行转化，对其主要产物进行分离纯化和结构鉴定，确认转化产生四个化合物，分别为：11-羟基-睾酮、6，11-羟基睾酮、6，11-羟基-雄甾烯二酮和11-羟基-18-氧杂D扩环雄甾烯二酮。     

齐墩果酸的微生物转化筛选及转化率的测定

目的通过RP-HPLC法检测25种真菌对齐墩果酸的转化情况,并对有转化的真菌菌种进行转化率的测定。方法采用Kromasil C18柱(250 mm×4.6 mm,5μm),流动相为甲醇-体积分数0.1%乙酸水溶液(体积比94∶6),柱温为室温,流速1.0 mL.min-1,检测波长210 nm。结果齐墩果酸质量浓度在10~80 mg.L-1内与峰面积呈良好线性关系,回归方程为A=6.778×106ρ-2.539×104(r=0.999 8)。经HPLC检测25种真菌中有5种真菌对齐墩果酸有转化,测得的转化率分别为56.2%、69.7%、77.9%、81.6%、83.0%。结论该法简便、准确、重现性好,适用于齐墩果酸转化的筛选及转化率的测定。     

Isolation and structural elucidation of biotransformation products from acarbose

Following oral administration the a-glucosidase inhibitor acarbose (O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl) -2-cyclohexen-1-yl]amino]-a-D-glucopyranosyl-(1----4)-O-a-D-glu copyranosyl-(1----4)-D-glucopyranose, Bay g 5421) is degraded by digestive enzymes and/or intestinal microorganism. The effect of anaerobic intestinal bacteria can be studied in an in vitro model which involves the incubation of acarbose with human or animal intestinal flora. Acarbose and nine biotransformation products can be isolated from the incubation mixture. These products were identified by nuclear magnetic resonance and mass spectrometry as so-called component 2 (loss of the terminal glucose), component 1 (loss of both glucose rings), hexose homologues of acarbose and component 2, methyl homologues of acarbose, butyric acid ester of component 2, basic disaccharide (loss of the cyclitol ring of component 2), delta-aminovaleric acid and gamma-aminobutyric acid. Following oral administration of [14C]-acarbose to healthy volunteers, 35% of the radioactivity was excreted in the form of at least 13 metabolites in the urine. Three of the metabolites were isolated by Craig countercurrent distribution and ion-pair HPLC and characterized by virtue of their nuclear magnetic resonance and mass spectra as derivatives of 4-methylpyrogallol. Two were shown to be monomethylether-monosulphates while the third was a monosulphate-monoglucuronide. The synthesis of ten reference substances and the comparison of HPLC and UV data clearly indicated that the majority of the non-isolated metabolites were also 4-methylpyrogallol derivatives. The peculiarities of the nuclear magnetic resonance and mass spectra of this type of compound are discussed.     

Natural products in therapy

A review is presented which shows the vegetable kingdom as an almost inexhaustible reservoir of potential drugs. Some historical aspects about the use of plants and their constituents in medicine are dealt with. A number of problems connected with the search for new prototype drugs of biological origin is reported as well as modern methods used in this promising research. Some examples are given concerning recent results of investigations of plants used in traditional and modern medicine in China. Special attention is paid to the present role of natural products in therapy: as biologically active compounds as such, as starting materials for (semi)synthetic drugs and, last but not least, as source of inspiration or as models for the synthesis of new drugs with better therapeutic, chemical or physical properties than the original compounds.     

Natural products in therapy

A review is presented which shows the vegetable kingdom as an almost inexhaustible reservoir of potential drugs. Some historical aspects about the use of plants and their constituents in medicine are dealt with. A number of problems connected with the search for new prototype drugs of biological origin is reported as well as modern methods used in this promising research. Some examples are given concerning recent results of investigations of plants used in traditional and modern medicine in China. Special attention is paid to the present role of natural products in therapy: as biologically active compounds as such, as starting materials for (semi)synthetic drugs and, last but not least, as source of inspiration or as models for the synthesis of new drugs with better therapeutic, chemical or physical properties than the original compounds.     

Natural marine anti-inflammatory products

The marine environment has been shown to be the source of a great diversity of chemical structures with promising biological activities. The isolation, biological evaluation, chemical properties and synthetic elaborations of the products of marine organisms and microorganisms have attracted the attention of organic chemists, medicinal chemists, biologists and pharmacists. Marine organisms and microorganisms have provided a large proportion of the natural anti-inflammatory products over the last years. Marine organisms include green algae, brown algae, red algae, sponges, coelenterates, bryozoans, molluscs, tunicates, echinoderms, miscellaneous marine organisms and marine microorganisms and phytoplankton. This review describes current progress in the development of a selection of new anti-inflammatory agents from marine sources. The chemistry and biological evaluation are discussed.     

Natural products in drug discovery

Natural products have been the single most productive source of leads for the development of drugs. Over a 100 new products are in clinical development, particularly as anti-cancer agents and anti-infectives. Application of molecular biological techniques is increasing the availability of novel compounds that can be conveniently produced in bacteria or yeasts, and combinatorial chemistry approaches are being based on natural product scaffolds to create screening libraries that closely resemble drug-like compounds. Various screening approaches are being developed to improve the ease with which natural products can be used in drug discovery campaigns, and data mining and virtual screening techniques are also being applied to databases of natural products. It is hoped that the more efficient and effective application of natural products will improve the drug discovery process.     

Natural products used for diabetes

OBJECTIVE: To review the efficacy and safety of natural products commonly used for diabetes. DATA SOURCES: English and Spanish-language journals retrieved through a MEDLINE search of articles published between 1960 and December 2001 using these index terms: Opuntia, karela, gymnema, tecoma, alpha lipoic acid, thioctic acid, ginseng, panaxans, and diabetes. DATA SYNTHESIS: Natural products have long been used in traditional systems of medicine for diabetes. Products in common use include nopal (prickly pear cactus), fenu-greek, karela (bitter melon), gymnema, ginseng, tronadora, chromium, and alpha-lipoic acid. The popularity of these products varies among people of different ethnicities. Nopal is the most commonly used herbal hypoglycemic among persons of Mexican descent. Karela is more commonly used by persons from Asian countries. Some of these agents have gained universal appeal. For a select number of products, studies have revealed single or multiple mechanisms of action. For several of these, high soluble fiber content is a contributing factor. CONCLUSION: Based on the available evidence, several natural products in common use can lower blood glucose in patients with diabetes. Commonly used natural products often have a long history of traditional use, and pharmacists who have a stronger understanding of these products are better positioned to counsel patients on their appropriate use.     

Natural products as drug leads

The clinical efficacy of natural products has been demonstrated for centuries. However, by using the active principles in such extracts as leads for conventional medicinal chemistry programmes it is possible to develop compounds with an improved therapeutic profile. Using an acrylic acid lead, with antidiabetic properties, it has been shown that the attachment of a thiazolidinedione group provides a more effective antidiabetic agent that does not produce weight gain in animals. In contrast, cyclic analogues of the acrylic acid retain the anti-inflammatory activity of the lead, but do not display antidiabetic activity.     

Natural products as aromatase inhibitors

With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purposes (e.g., botanical dietary supplements) may also afford AIs with reduced side effects. A thorough review of the literature regarding natural product extracts and secondary metabolites of plant, microbial, and marine origin that have been shown to exhibit aromatase inhibitory activity is presented herein.     

Natural products as angiogenesis modulators

Cancer remains one of the major causes of death worldwide. Anti-angiogenic therapy is one of the new approaches to anticancer therapy. Out of 22 angiogenesis inhibitors currently under clinical trials there are 11 natural products or were modeled on a natural product parent. This review shows the potential of natural products for the discovery of new anti-angiogenic leads.     

Investigations on the biotransformation of mebendazole using an isolated perfused rat gut system

1. The intestinal metabolism of the benzimidazole, mebendazole (MEB), has been investigated using isolated perfused jejunal segments of rats. Significant absorption and intestinal metabolism of the substance was observed.

2. The metabolites, the reduced α-hydroxy-analogue, its glucuronide, and the decarbamoylated 2-amino-analogue, were transported into the resorbate collected at the serosal side or were resecreted into the gut lumen.

3. The intestinal decarbamoylation of mebendazole increased up to 20-fold after pretreatment with 3-methylcholanthrene (MC), and complete re-secretion of this metabolite into the gut lumen led to a total loss of the absorption of mebendazole and metabolites across the gut wall.

4. The results indicate the ability of the gut to metabolize mebendazole by phase I and II reactions.

5. An almost complete loss of bioavailability after induction of the gut enzyme system by MC was observed.     

The acetylcholinesterase inhibitory activity of metoclopramide and some of its biotransformation products

K_i values were determined for thein vitro acetylcholinesterase inhibitory activity of the anti-emetic metoclopramide, some of its metabolic products and the newly synthesised N-(ethyl)-4-chlorobenzamide (1). Metoclopramide was a moderate inhibitor, 113 times more potent than 1 and 50 times less potent than physostigmine. Metabolic products of N-de-ethylation, N-di-de-ethylation, deamination followed by reduction and amide hydrolysis were increasingly less active as inhibitors. The implications of the present findings are briefly discussed.